In EP-A-0,348,522; Nature 1990, 343, 470; J. Med. Chem. 1991, 34, 746; and The Lancet 1991, 338, 140 there are described 4,5,6,7-tetrahydroimidazo[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-thiones (TIBO) derivatives with potent activity against human immunodeficiency virus 1 (HIV- 1) in vitro and showing encouraging results in vivo. A significant limitation to further assessment and eventual large-scale production of these novel drugs has hitherto been their long, difficult and insufficient synthesis. The fundamental problem in all approaches to the title compounds reported up till now relates to the use of benzoic acid derivatives and/or amino acid derivatives as starting materials. All said approaches necessarily involve one or two amide-to-amine reduction steps with violently reacting reagents such as lithium aluminum hydride or borane derivatives. Whereas such approaches may be suitable in the laboratory, (e.g. J. Org. Chem. 1991, 56, 4600), they are hardly amenable to large-scale production. In case enantiomeric amino acid derivatives are used as starting materials, the problems are further compounded by the possibility of racemisation at the chiral carbon atom.
The present invention is concerned with an improved process for preparing particular TIBO derivatives that avoids all problematic amide-to-amine reductions and rules out any possibility of racemisation at the chiral carbon atom. The process according to the present invention also represents a short and efficient industrial approach to particular TIBO compounds reported hitherto.